Early-Onset “Drusenoid” Macular Dystrophies
Early-onset drusen typically manifests at younger ages than do drusen in most cases of AMD. Though they are frequently referred to as “familial or autosomal dominant drusen,” the clinician needs to establish whether other family members are affected before assuming an inheritance pattern. In addition, although early-onset drusen are presumed to be genetically determined, the inheritance pattern in the majority of young patients is never established; many cases may be multigenic and related to the same pathways that give rise to AMD.
Drusen are usually numerous and vary in size, typically extending beyond the vascular arcades and nasal to the optic nerve head (Fig 13-17). Early-onset drusen have been classified into 3 entities: (1) large colloid drusen, (2) Malattia Leventinese, and (3) cuticular drusen (Fig 13-18). On fundus examination, large colloid drusen appear as large, yellowish, and bilateral lesions located in the macula and/or the periphery of the retina. The vitelliform lesions are hyperautofluorescent and are thought to be made up of lipofuscin, while the associated surrounding cuticular drusen and/or subretinal drusenoid deposits are generally not autofluorescent. Malattia Leventinese and Doyne honeycomb dystrophy are essentially the same condition and often show a distinctive pattern of radial extensions of small and intermediate-sized deposits emanating from the fovea. The condition is caused by a shared single autosomal dominant mutation in the gene EFEMP1, which to date has not been associated with AMD risk. However, the causative genes in several juvenile and early-onset macular dystrophies are the same as the genes that have been implicated in the complex genetic disorder of AMD.
Sorsby macular dystrophy (SMD), a dominantly inherited disease resulting from TIMP3 mutations, involves the development of bilateral, subfoveal, choroidal neovascular lesions at approximately 40 years of age (Fig 13-19). As the macular lesions evolve, they take on the appearance of geographic atrophy, with pronounced clumps of black pigmentation around the central ischemic and atrophic zone (a pseudoinflammatory appearance). An early sign of the disease is the presence of numerous fine drusenlike deposits or a confluent plaque of faintly yellow material beneath the RPE of the posterior pole. Both common and rare variants of TIMP3 have been implicated in the pathogenesis of AMD. Other drusenlike deposits that manifest before age 50 include those associated with several hereditary basement membrane abnormalities that lead to significant renal disease, including Alport syndrome, membranoproliferative glomerulonephritis type II, and atypical hemolytic uremia syndromes. Recognition of these conditions and confirmation with molecular genetic testing is critical because of the initial occult nature of the renal disease, which can be life-threatening. The genes known to lead to these Mendelian disorders are also implicated in the causation of AMD.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.